The proposed research is a multidisciplinary, multicenter, collaborative study to continue the investigation of the clinical, cardiac, and genetic aspects of the Long QT Syndrome (LQTS) - a heritable channelopathy with delayed ventricular repolarization and episodic malignant arrhythmias manifest by syncope and sudden death. Presently, over 300 mutations on 6 ion-channel genes (KCNQ1, HERG, SCNhA, minK, MIRP1, and KCNJ2) have been identified in LQTS. The five-year research activity will: 1) continue to upgrade, expand, and collect clinical and genetic data on 900 active LQTS families (5,508 active family members) currently enrolled in the LQTS Registry; 2) develop a multivariate prognostic risk-scoring system using different time origins (from birth, and from age 10, 20, and 40 years); 3) evaluate the effectiveness and limitations of LQTS therapies; and 4) expand investigations into LQTS genotype-phenotype relationships. Functionally, the grant has four sections: a clinical section involving six clinical centers that have enrolled and are actively following the LQTS families in the Registry; a genotype section involving four experienced molecular genetic laboratories; a biostatistical section that will provide expertise in study design and statistical data analyses; and a central coordination and data center that will provide data management and coordination of the various components of the program. This integrated research program offers a substantial prospect of: 1) improving the diagnosis, management, and treatment of individuals affected with LQTS; and 2) providing a fundamental understanding of the molecular basis of repolarization-related cardiac arrhythmias in patients with a broad spectrum of cardiac disorders.